Aims: Fibromyalgia (FM) is a chronic pain syndrome frequently associated with muscular oxidative stress and mitochondrial dysfunction. This study investigated the therapeutic potential of Coenzyme Q10 (CoQ10) supplementation in a reserpine-induced FM rat model, focusing on its effects in gastrocnemius and soleus muscles. Materials and methods: Female Wistar rats were divided into Control, FM, CoQ10, and FM + CoQ10 groups. Reserpine (1 mg kg−1 day−1, s.c.) was administered for 3 days to induce FM; CoQ10 (150 mg kg−1 day−1, oral gavage) was given for 7 days. Cold hyperalgesia, serum TNF-α, muscular CoQ9/CoQ10 levels, oxidative stress markers (MDA, PC, TOS), antioxidant defenses (SOD, GSH, TAC), and mRNA expression of AMPK, SIRT1, PGC-1α, and FNDC5 were assessed. Key findings: Reserpine successfully induced cold hyperalgesia and increased serum TNF-α. In both muscle types of FM rats, CoQ10 levels were depleted, oxidative damage markers were elevated, and antioxidant defenses (GSH, SOD) were compromised. CoQ10 supplementation attenuated cold hyperalgesia, normalized muscular CoQ10 (and influenced CoQ9), significantly reduced MDA, PC, and TOS levels, and partially restored GSH and SOD activity. Notably, CoQ10 robustly upregulated the mRNA expression of AMPK, SIRT1, and PGC-1α, key regulators of mitochondrial biogenesis, in both gastrocnemius and soleus muscles. Furthermore, CoQ10 significantly increased the expression of FNDC5, the precursor to the myokine irisin. Significance: These findings suggest that CoQ10 ameliorates reserpine-induced FM-like pathology by mitigating oxidative stress, enhancing antioxidant capacity, promoting mitochondrial biogenesis, and stimulating the FNDC5/irisin pathway in skeletal muscle, highlighting its multifaceted therapeutic potential for FM.